Report Mapping of Charcot-Marie-Tooth Disease Type
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 70:244–250, 2002 Report Mapping of Charcot-Marie-Tooth Disease Type 1C to Chromosome 16p Identifies a Novel Locus for Demyelinating Neuropathies Valerie A. Street,1 Jeff D. Goldy,2 Alana S. Golden,5 Bruce L Tempel,1 Thomas D. Bird,3,4,6 and Phillip F. Chance2,3 1V. M. Bloedel Hearing Research Center, Department of Otolaryngology–Head and Neck Surgery, 2Departments of Pediatrics, 3Neurology, and 4Medicine, and 5Undergraduate Neurobiology Research Program, University of Washington, and 6VA Puget Sound Health Care System, Seattle Charcot-Marie-Tooth (CMT) neuropathy represents a genetically heterogeneous group of diseases affecting the peripheral nervous system. We report genetic mapping of the disease to chromosome 16p13.1-p12.3, in two families with autosomal dominant CMT type 1C (CMT1C). Affected individuals in these families manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes, sensory impairment, slow nerve conduction velocities, and nerve demyelination. A maximal combined LOD score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in these two families localizes the CMT1C gene within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in these two pedigrees are not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. The epithelial membrane protein 2 gene (EMP2), which maps to chromosome 16p13.2, was evaluated as a candidate gene for CMT1C. Charcot-Marie-Tooth disease (CMT; also known as “he- 145900), also known as “Dejerine-Sottas disease,” may reditary motor and sensory neuropathy”) is a group of be inherited as an autosomal recessive or autosomal disorders characterized by degenerative changes in pe- dominant trait and is characterized by severe hypomye- ripheral motor and sensory nerves. CMT is transmitted lination, markedly reduced NCVs, and infantile onset most frequently in an autosomal dominant manner and (Lyon 1969; Kennedy et al. 1977). CMT4 is inherited affects ∼1 in 2,000 individuals (Skre 1974), making it as an autosomal recessive trait, with patients displaying one of the most common inherited neurological diseases. early disease onset and rapid distal limb atrophy (Ben CMT leads to progressive distal muscle weakness af- Othmane et al. 1993). In addition to autosomal forms fecting the upper and lower limbs, with loss of sensation. of CMT, X-linked dominant inheritance also has been Clinical signs may range from a lack of symptoms to well characterized (Bergoffen et al. 1993). marked muscle weakness, and, in rare cases, patients On the basis of genetic-linkage and gene-sequence may become wheelchair dependent. analysis, CMT1 has been divided into four subtypes. CMT type I (CMT1) is characterized by demyelina- CMT1A (MIM 118220) is associated with a 1.4-Mb tion and reduced (!40 m/s) nerve conduction velocities duplication on chromosome 17p11.2-p12 (Lupski et al. (NCVs) (Dyck and Lambert 1968). In CMT type II 1991; Raeymaekers et al. 1991) with a gene-dosage ef- fect for peripheral myelin protein (PMP-22 [MIM (CMT2), there is axonal loss, with normal or only mildly 601097]) (Matsunami et al. 1992; Patel et al. 1992; Tim- reduced NCVs (Dyck and Lambert 1968). CMT3 (MIM merman et al. 1992; Valentijn et al. 1992b; Warner et Received August 3, 2001; accepted for publication October 5, 2001; al. 1996). PMP-22 point mutations have been found in electronically published November 16, 2001. rare patients with CMT1A who lack the duplication Address for correspondence and reprints: Dr. Phillip Chance, Di- (Valentijn et al. 1992a; Roa et al. 1993; Nelis et al. vision of Genetics and Development, Department of Pediatrics, 1994). CMT1B (MIM 118200) results from mutations Box 356320, University of Washington, Seattle, WA 98195. E-mail: in the gene on chromosome 1 encoding myelin protein [email protected] ᭧ 2002 by The American Society of Human Genetics. All rights reserved. zero (MPZ [MIM 159440]; also known as “Po pro- 0002-9297/2002/7001-0023$15.00 tein”), a major structural protein of peripheral mye- 244 Figure 1 Haplotype analysis in pedigrees K1550 (A) and K1551 (B). Affected individuals are denoted by blackened symbols, males are denoted by squares, females are denoted by circles, and deceased persons are indicated by a diagonal line through a symbol. Markers are listed from telomere (top) to centromere (bottom) and are the same in both pedigrees. The CMT1C-linked haplotype is boxed. 246 Am. J. Hum. Genet. 70:244–250, 2002 Table 1 Pedigrees K1550 and K1551: LOD Scores with Chromosome 16p Markers LOD SCORE AT RECOMBINATION FRACTION (v) p MARKER (POSITION) a AND PEDIGREE .0 .01 .05 .1 .2 .3 .4 Zmax vmax D16S404 (16.7): K1550 Ϫϱ .46 1.56 1.79 1.60 1.11 .53 1.793 .114 K1551 Ϫϱ 3.07 4.03 4.07 3.44 2.43 1.18 4.105 .076 K1550ϩK1551 Ϫϱ 3.53 5.59 5.86 5.04 3.54 1.71 D16S519 (19.7): K1550 3.62 4.83 5.07 4.78 3.83 2.65 1.34 5.083 .038 K1551 Ϫϱ 3.37 3.70 3.53 2.80 1.86 .80 3.706 .046 K1550ϩK1551 Ϫϱ 8.20 8.77 8.31 6.63 4.51 2.14 D16S307 (21.8): K1550 3.27 3.20 2.91 2.54 1.81 1.11 .50 3.270 .000 K1551 4.07 4.00 3.71 3.32 2.47 1.56 .66 4.070 .000 K1550ϩK1551 7.34 7.20 6.62 5.86 4.28 2.67 1.66 D16S310 (23.1): K1550 5.74 5.64 5.25 4.74 3.67 2.53 1.32 5.740 .000 K1551 5.58 5.48 5.06 4.51 3.35 2.11 .84 5.580 .000 K1550ϩK1551 11.32 11.12 10.31 9.25 7.02 4.64 1.40 D16S500 (27.0): K1550 6.97 6.86 6.39 5.80 4.53 3.16 1.67 6.970 .000 K1551 7.28 7.15 6.64 5.96 4.53 2.96 1.3 7.280 .000 K1550ϩK1551 14.25 14.01 13.03 11.76 9.06 6.12 2.97 D16S764 (28.7): K1550 Ϫϱ 3.59 3.92 3.76 3.08 2.21 1.19 3.923 .047 K1551 2.93 2.89 2.69 2.41 1.79 1.07 .35 2.930 .000 K1550ϩK1551 Ϫϱ 6.48 6.61 6.17 4.87 3.28 1.54 D16S310 (31.1): K1550 Ϫϱ 4.00 4.31 4.10 3.32 2.35 1.25 4.310 .043 K1551 Ϫϱ Ϫ.26 .89 1.16 1.06 .70 .31 1.180 .125 K1550ϩK1551 Ϫϱ 3.74 5.20 5.26 4.38 3.05 1.56 a Markers are shown in order given by Dib et al. (1996), from telomere to centromere. Marker map positions (in cM) are based on the Ge´ne´thon and Marshfield human sex-averaged linkage maps. lin (reviewed by Lupski [1998]). The CMT1C (MIM for CMT1, including distal muscle weakness and atro- 300200) designation was suggested on the basis of ge- phy, depressed deep-tendon reflexes, and sensory im- netic evidence, when linkage to regions on chromosomes pairment (Dyck and Lambert 1968). The mean ulnar 17 and 1 were excluded in two CMT1 pedigrees (K1550 (16.7 m/s [n p 3 ] and 25.3 m/s [n p 8 ], for K1550 and and K1551) (Chance et al. 1990, 1992). The CMT1D K1551, respectively), median (23 m/s [n p 5 ] and 25.8 gene maps to chromosome 10 and is associated with m/s [n p 12 ]), and peroneal (20.4 m/s [n p 4 ], 21 m/s mutations in the early growth response 2 gene (EGR2 [n p 6 ]) motor-nerve conduction velocities of affected [MIM 129010]), also known as “Krox-20” (Warner et K1550 and K1551 individuals are consistent with al. 1998). In the present article, we describe the mapping CMT1. One affected person (individual 2.7) in pedigree of the CMT1C locus to chromosome 16 and the eval- K1550 was examined further, by sural-nerve biopsy, uation of the epithelial membrane protein 2 gene (EMP2 which demonstrated “onion bulb hypertrophy” typical [MIM 602334]) as a candidate gene. of demyelinating CMT. Under a protocol of informed consent approved by A genomewide scan (ABI PRISM Linkage Mapping the institutional review board of the University of Wash- Set Version 2; PE Biosystems) was performed in pedi- ington, Seattle, 15–20 ml of blood were drawn, by ve- grees K1550 and K1551, with informative microsatellite nipuncture, to obtain high-molecular-weight DNA, as markers (Dib et al. 1996) spaced at ∼10-cM intervals. described previously (Neitzel 1986). Pedigrees K1550 PCR was performed under the conditions recommended and K1551 are of Irish and English descent, respectively, by the manufacturer (PE Biosystems). PCR products and are depicted in figures 1A and B, respectively. Male- were multiplexed and separated by capillary electropho- to-male transmission is observed in both families, con- resis using an ABI PRISM 310 Genetic Analyzer (PE firming autosomal dominant inheritance. Affected in- Biosystems). Microsatellite marker-allele data were an- dividuals in both pedigrees met widely accepted criteria alyzed by GENESCAN version 3.1.2 and GENOTYPER Reports 247 16p13.1-p12.3, in both pedigrees (table 1). Haplotype analysis indicated that three markers—D16S3075, D16S3102, and D16S500—were nonrecombinant with the CMT1C phenotype in family K1550 (fig. 1A). In- dividual 2.4 displayed a crossover between markers D16S519 and D16S3075, defining D16S519 as a distal flanking marker.